ABSTRACT
We evaluated the potential for a monoclonal antibody antagonist of the glucagon receptor (Ab-4) to maintain glucose homeostasis in type 1 diabetic rodents. We noted durable and sustained improvements in glycemia which persist long after treatment withdrawal. Ab-4 promoted ß-cell survival and enhanced the recovery of insulin+ islet mass with concomitant increases in circulating insulin and C peptide. In PANIC-ATTAC mice, an inducible model of ß-cell apoptosis which allows for robust assessment of ß-cell regeneration following caspase-8-induced diabetes, Ab-4 drove a 6.7-fold increase in ß-cell mass. Lineage tracing suggests that this restoration of functional insulin-producing cells was at least partially driven by α-cell-to-ß-cell conversion. Following hyperglycemic onset in nonobese diabetic (NOD) mice, Ab-4 treatment promoted improvements in C-peptide levels and insulin+ islet mass was dramatically increased. Lastly, diabetic mice receiving human islet xenografts showed stable improvements in glycemic control and increased human insulin secretion.
Subject(s)
Antibodies, Monoclonal/pharmacology , Diabetes Mellitus, Experimental/therapy , Glucagon-Secreting Cells/drug effects , Hypoglycemic Agents/pharmacology , Insulin-Secreting Cells/drug effects , Receptors, Glucagon/antagonists & inhibitors , Animals , Blood Glucose/metabolism , C-Peptide/metabolism , Cell Lineage/drug effects , Cell Transdifferentiation/drug effects , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/immunology , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/therapy , Gene Expression , Glucagon/antagonists & inhibitors , Glucagon/metabolism , Glucagon-Secreting Cells/metabolism , Glucagon-Secreting Cells/pathology , Humans , Insulin/metabolism , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Islets of Langerhans/metabolism , Islets of Langerhans/physiology , Islets of Langerhans Transplantation , Mice , Mice, Inbred NOD , Organ Size/drug effects , Receptors, Glucagon/genetics , Receptors, Glucagon/metabolism , Treatment OutcomeABSTRACT
Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to α cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for α cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human α cells was mTOR and FoxP transcription factor dependent. Changes in hepatic amino acid (AA) catabolism gene expression predicted the observed increase in circulating AAs. Mimicking these AA levels stimulated α cell proliferation in a newly developed in vitro assay with L-glutamine being a critical AA. α cell expression of the AA transporter Slc38a5 was markedly increased in mice with interrupted glucagon signaling and played a role in α cell proliferation. These results indicate a hepatic α islet cell axis where glucagon regulates serum AA availability and AAs, especially L-glutamine, regulate α cell proliferation and mass via mTOR-dependent nutrient sensing.
